The hypothesis that the pancreatic beta cell is a primary site of pathology in human and experimental diabetes, and the knowledge that the beta cell population is affected by genetic background and responds to immunologic injury has directed our attention to the need for further study of spontaneous models of diabetes mellitus. This request is for support of research projects designed to study the pathogenesis of diabetes in a unique model of insulin- dependent diabetes, the Bio Breeding/Worcester (BB/W) rat. Support is requested for breeding and related experiments designed to establish inbred lines of diabetes-prone and diabetes- resistant BB/W rats and to define the genetic basis of the syndrome. Support is requested for studies of the cellular mechanism of beta cell destruction and of the resistance to beta injury. Islet transplantation and adoptive transfer experiments will explore the role of MHC restriction in the destruction of pancreatic beta cells. Virtually all of the proposed experiments are immunopathologic in nature. As such, all incorporate essential morphologic read out systems including routine light microscopy, immunohistochemistry and electron microscopy of tissues as well as flow cytometry techniques for the identification of lymphocyte subsets.